Wild mouse species and the various inbred laboratory mouse strains differ from one another in their susceptibility to the mouse gammaretroviruses and retrovirus-induced cancers. These differences are due to variations in specific host genes, and we have been engaged in an ongoing effort to identify and characterize several host genes that are either involved in virus resistance or that contribute to the disease process. The mouse genome contains copies of mouse gammaretrovirus genomes, many of which can produce infectious and pathogenic viruses. There are also host factors that interfere directly with virus infection and replication, and we focus our efforts on those factors that inhibit virus entry and the early post-entry stages of the virus replicative cycle. At the level of entry, resistance can be caused by polymorphisms in the cell surface receptor. After the gammaretrovirus enters the receptive cell, reverse transcription and translocation to the nucleus can be inhibited or altered by virus resistance factors Fv1, mApobec/Rfv3, and TRIM5alpha. Our current aim is to characterize these resistance factors and the viruses they target, define the origin and extent of antiviral activity in Mus evolution, and elucidate the responsible mechanisms. This work relies heavily on wild mice because laboratory strains provide only a limited sampling of the genetic diversity in Mus. Also, wild mouse species allow us to examine survival strategies in natural populations that harbor virus and to follow the evolution of the resistance genes. These mice additionally provide a source of novel resistance genes and virus variants. One set of projects aims to identify viral and cell receptor determinants responsible for virus binding and entry. We are currently working on the XPR1 receptor for the xenotropic/polytropic mouse leukemia viruses (XP-MLVs). We have determined that, in mouse populations exposed to infectious virus, virus resistance is mediated by polymorphisms of the cell surface receptor. We have now identified a total of six XPR1 susceptibility variants in wild mice and described the geographic and species distribution of these Mus Xpr1 variants. Five of these receptors restrict entry by two or more of the virus host range variants that rely on XPR1, and all of these receptors evolved in populations exposed to X-MLVs. Because XPR1 orthologs are found in all eukaryotes, and because all mammals but the laboratory mouse have X-MLV susceptible receptors, we looked for naturally occurring restrictive receptors in a related set of species outside the mammalian lineage. We found restrictive receptors in chickens as well as in other fowl and raptor species, and demonstrated that the gene is under positive selection in the avian lineage which is evidence of genetic conflicts that can result from antagonistic interactions with pathogens. All of the birds with disabling mutations are native to areas of Asia populated by the virus-infected mouse species M. m. castaneus, suggesting that contact between these species favored selection of mouse virus-resistant receptors in the birds. In another series of experiments, we have been using phylogenetic and molecular biological methods to identify the wild mouse origins of the endogenous XP-MLVs found in the sequenced C57BL mouse genome. Laboratory strains like C57BL are mosaics of 3 M. musculus subspecies: domesticus represents 95% of the lab mouse genome, musculus contributed 5%, and castaneus contributed 1%. The xenotropic endogenous retroviruses (ERVs) were all identified in Japanese mice, and all of them were embedded in musculus or castaneus segments of the genome indicating an Asian origin. In contrast, none of the 31 polytropic ERVs could be traced to wild mouse, including M. m. domesticus which carries dozens of P-MLV ERVs. This level of insertional polymorphism is surprising for a set of ERVs not known to be expressed as infectious virus, and is under further investigation. A few mouse leukemia viruses of ecotropic (mouse-tropic) host range are cytopathic, and these few viruses have restricted host range. We forced passaged one of these cytopathic viruses in restrictive cells and isolated a novel variant that has broad mouse-tropic host range, and is cytopathic in all mouse cells. We identified a single second site mutation in the envelope glycoprotein of this virus responsible for its expanded host range. This site is not positioned within the receptor binding pocket of the envelope glycoprotein, but is at the apex of this glycoprotein, where it is likely to have secondary contacts with the receptor.